PROJECT SUMI\(IARY (See instructions): The oropharynx is central to Kaposi sarcoma-assocaited herpesvirus (KSHV) infection; it is the primary site of viral replication, and saliva is the major route of KSHV transmission. Uncontrolled KSHV infection is associated with progression to KS. Some immunocompetent KSHV-infected people have frequent, high quantity oral replication, whereas others either rarely or never shed KSHV in saliva. This striking difference in the ability to control oral KSHV infection has clear implications for viral transmission, but may also be important for disease progression, since oral replication is strongly correlated with subsequent KSHV viremia and dissemination within the host. KSHV replication and development of KS occur much more often among people with HIV and other immunodeficiencies, which demonstrates the critical role of the immune system for preventing KSHV-associated disease. It is unknown, however, which immune responses to KSHV are most relevant for controlling infection. Despite the importance of the oral cavity in KSHV infection, mucosal immunity against KSHV has not been well studied. Neither is it understood how HIV infection and antiretroviral therapy (ART) affect oral immune responses to KSHV. The overall goal of this project is to identify correlates of the mucosal immune response associated with control of oral KSHV infection and viremia, and define how they are impaired by HIV infection. In Aim 1, mucosal immune effector mechanisms mediating control of KSHV infection in the oral cavity and blood will be identified. Cohorts of KSHV infected/ HIV-negative people infection will be followed in Uganda to quantify the levels of KSHV detected in saliva and blood, and correlate them with: (1) neutralizing antibody in saliva; (2) gama delta+ T cell responses; and (3) innate immune mediators in saliva. In Aim 2, the effect of untreated HIV infection on mucosal immune responses to KSHV will be evaluated by comparing the frequency and strength of the immune effector mechanisms described in HIV-uninfected people in Aim 1 to those in a second cohort of HIV-infected/ART naive subjects. Finally, in Aim 3, it will be determined whether ART is able to normalize mucosal immune responses to KSHV bv following HIV-infected subiects before and after initiation of ART.